CN104276992A - 一种奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)-乙酰胺的合成新工艺 - Google Patents

一种奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)-乙酰胺的合成新工艺 Download PDF

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CN104276992A
CN104276992A CN201410473452.1A CN201410473452A CN104276992A CN 104276992 A CN104276992 A CN 104276992A CN 201410473452 A CN201410473452 A CN 201410473452A CN 104276992 A CN104276992 A CN 104276992A
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oxiracetam
alkali
key intermediate
synthesis process
ethanamide
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CN104276992B (zh
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叶青
高建荣
任锋
李郁锦
韩亮
顾凯
钟健
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms

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Abstract

本发明提供了一种以4-卤代乙酰乙酸酯和甘氨酰胺盐酸盐为原料，通过“一锅法”制备奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)乙酰胺的新合成工艺，具有反应步骤少，收率高，原料廉价易得，后处理简单，三废少等优点。

Description

一种奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)-乙酰胺的合成新工艺
技术领域
本发明涉及制备奥拉西坦关键中间体2-（2,4-二氧代吡咯烷-1-基）-乙酰胺的新制备方法。
背景技术
奥拉西坦（Oxiracetam），化学名称：4-羟基吡咯烷酮-2-乙酰胺，分子式：C6H10N2O3，结构如1所示：
1
奥拉西坦是一种合成的羟基氨基丁酸(GABOB)环状衍生物，又称奥拉酰胺、羟氧吡醋胺，商品名有neuromet、Heupan、健朗星等，由意大利史克比切姆公司于1974年首次合成，并于1987年在意人利上市，是美国FDA批准的用于治疗老年痴呆的药物之一，目前报道的合成路线普遍存在着提纯困难或合成路线长等缺点。如日本专利JP62026267中提出的一种以3-羟基-4-卤代丁酸乙酯和甘氨酰胺为原料一步成环法直接制备奥拉西坦，虽然路线较短，但这种方法中副反应多，反应产物成分复杂，需柱层析提纯，且精制后不能完全达到药用标准，另外还存在着反应时间长，收率低等缺点。
 
中国专利CN101121688A报道了以双乙烯酮经氯化开环，甲基化、与甘氨酸缩合并进一步关环、酯化、氨解、脱甲基得到中间体2-(2,4-二氧代吡咯烷-1-基)乙酰胺，再经过KBH4还原得到奥拉西坦的合成方法。
 
由于该合成路线中各步反应选择性较高，且相关中间体可以进行有效提纯，因此较易得到高纯度的奥拉西坦产品，但是其中间体2-(2,4-二氧代吡咯烷-1-基)乙酰胺（结构见2）的合成步骤长，
收率较低，仅为35%，目前缺少该中间体的高效合成方法，因此有必要对其合成方法进行探索，获得一条适合于工业化生产的、高效的合成该中间体的方法。
                                        2
发明内容
鉴于目前奥拉西坦合成关键中间体2-(2,4-二氧代吡咯烷-1-基)-乙酰胺缺少高效的合成方法，本发明提供了一种原材料廉价易得、反应步骤短、操作简便、收率高、三废少、适合于工业化生产的2-(2,4-二羰基吡咯烷酮-1-基)-乙酰胺的新合成工艺，技术方案如下：
4-卤代乙酰乙酸酯与甘氨酰胺盐酸盐在碱的存在下缩合得到2-(2,4-二氧代吡咯烷-1-基)-乙酰胺的反应方程式为：
本发明中， X为Br, Cl，优选Cl; R为甲基，乙基，丙基和丁基, 优选乙基。所用溶剂为甲醇，乙醇，丙醇或异丙醇等极性溶剂，优选乙醇。所用碱为碳酸钠，碳酸氢钠，碳酸钾和碳酸氢钾等无极碱，优选碳酸钾。所用4-卤乙酰乙酸酯与甘氨酰胺盐酸盐的投料摩尔比为1:1~1.8，优选为1:1~1.3。所用碱与4-卤乙酰乙酸酯的投料摩尔比为1:2.0~3.0倍，优选为1: 2.2 ~2.6。反应温度为40~100℃，优选60~80℃,反应时间为1~8小时，优选4~6小时。
与现有技术相比，本发明所述制备方法的优点在于所述的奥拉西坦中间体2-(2,4-二氧代吡咯烷-1-基)-乙酰胺的合成工艺具有步骤短，操作简便，原料廉价易得，收率高、三废少等优点。因此具有非常好的工业应用前景。
具体实施方式：
下面结合具体实施例对本发明做进一步的说明。
实施例：
在三口烧瓶中，加入8.0 g（0.075mol）甘氨酰胺盐酸盐，20.2 g（0.029mol）碳酸钾，100 ml无水乙醇，在45℃下搅拌30分钟, 缓慢滴加10 g（0.06 mol）4-氯乙酰乙酸乙酯，滴完回流反应5h。，趁热过滤，减压脱除部分乙醇，残留物冷却过滤，得到2-(2,4-二羰基吡咯烷酮-1-基)-乙酰胺关键中间体6.7 g, 收率72.0%。1H NMR (500 MHz, DMSO-d 6 ) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 4.65 (s, 2H), 4.48 (s, 1H), 3.67 (d, J = 5.6 Hz, 2H)；13C NMR (125 MHz, DMSO-d 6 ) δ 174.71 (s), 169.90 (s), 168.97 (s), 79.37 (s), 67.16 (s), 46.90 (s)；GC/MS：m/z=156 [M]+。

Claims (6)

1.一种制备奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)-乙酰胺的合成新方法，其特征在于4-卤代乙酰乙酸酯与甘氨酰盐酸盐在碱的作用缩合得到2-（2,4-二氧代吡咯烷-1-基）乙酰胺，反应式如下：
。
2.如权利要求1所述的方法，4-卤代乙酰乙酸酯优选4-氯乙酰乙酸乙酯。
3.如权利要求1所述的方法，反应采用的碱优选碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾等无机碱。
4.如权利要求1~3任一项所述的方法， 4-卤代乙酰乙酸酯与甘氨酰胺盐酸盐的投料摩尔优选1~1.3:1。
5.如权利要求1~3任一项所述的方法，碱与4-卤乙酰乙酸酯的投料摩尔比优选2.2 ~2.6:1。
6.如权利要求1~3任一项所述的方法，反应温度优选60~80 ℃。
CN201410473452.1A 2014-09-17 2014-09-17 一种奥拉西坦关键中间体2‑(2,4‑二氧代吡咯烷‑1‑基)‑乙酰胺的合成工艺 Active CN104276992B (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725294A (zh) * 2015-03-25 2015-06-24 浙江工业大学 一种奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)乙酸乙酯的合成新方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6226267A (ja) * 1985-07-26 1987-02-04 Denki Kagaku Kogyo Kk オキシラセタムの製造法
US4849528A (en) * 1986-06-26 1989-07-18 Lonza Ltd. 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
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JPS6226267A (ja) * 1985-07-26 1987-02-04 Denki Kagaku Kogyo Kk オキシラセタムの製造法
US4849528A (en) * 1986-06-26 1989-07-18 Lonza Ltd. 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide

Non-Patent Citations (2)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725294A (zh) * 2015-03-25 2015-06-24 浙江工业大学 一种奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)乙酸乙酯的合成新方法
CN104725294B (zh) * 2015-03-25 2018-05-29 浙江工业大学 一种奥拉西坦关键中间体2-(2,4-二氧代吡咯烷-1-基)乙酸乙酯的合成新方法

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